N,N′-Bis[(E)-4-nitro­benzyl­idene]-4,4′-oxydianiline

The title compound, C26H18N4O5, can be regarded as an extended ether with two terminal nitro groups. The two aryl rings bonded to the central O atom form a dihedral angle of 75.72 (6)°, and the terminal nitro groups are slightly twisted [by 6.4 (2) and 3.3 (3)°] from the benzene rings to which they are attached. The crystal packing exhibits weak inter­molecular C—H⋯O hydrogen bonds and π–π inter­actions [centroid–centroid distances = 3.794 (3) Å]

Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression

CIITA activates the expression of multiple genes involved in antigen presentation and it is believed to be required for both constitutive and IFN\xce\xb3-inducible expression of these genes. To understand the role of CIITA in vivo, we have used gene targeting to generate mice that lack CIITA. CIITA-deficient (-/-) mice do not express conventional MHC class II molecules on the surface of splenic B cells and dendritic cells. In addition, macrophages resident in the peritoneal cavity do not express MHC class II molecules upon IFN\xce\xb3 stimulation nor do somatic tissues of mice injected with IFN\xce\xb3, in contrast with wild-type mice. The levels of li and H-2M gene transcripts are substantially decreased but not absent in CIITA (-/-) mice. The transcription of nonconventional MHC class II genes is, however, not affected by CIITA deficiency. A subset of thymic epithelial cells express MHC class II molecules. Nonetheless, very few mature CD4 T cells are present in the periphery of CIITA (-/-) mice despite MHC class II expression in the thymus. Consequently, CIITA (-/-) mice are impaired in T-dependent antigen responses and MHC class II-mediated allogeneic reponses

A Novel Method for Measuring the Burden of Breast Cancer in Neighborhoods

Community-based breast cancer prevention efforts often focus on women who live in the same neighborhoods, as they tend to have similar demographic characteristics, health behaviors, and environmental exposures; yet little research describes methods of selecting neighborhoods of focus for community-based cancer prevention interventions. Studies frequently use demographics from census data, or single breast cancer outcomes (e.g., mortality, morbidity) in order to choose neighborhoods of focus for breast cancer interventions, which may not be optimal. This study presents a novel method for measuring the burden of breast cancer among neighborhoods that could be used for selecting neighborhoods of focus. In this study, we 1) calculate a metric composed of multiple breast cancer outcomes to describe the burden of breast cancer in census tracts Philadelphia, PA, USA; 2) map the neighborhoods with the greatest breast cancer burden; and 3) compare census tracts with the highest burden of breast cancer to those with demographics sometimes used for geo-based prioritization, i.e., race and income. The results of our study showed that race or income may not be appropriate proxies for neighborhood breast cancer burden; comparing the breast cancer burden with demographics at the census tract level, we found few overlaps with the highest percentage African American or the lowest median incomes. Agencies implementing community-based breast cancer interventions should consider this method to inform the selection of neighborhoods for breast cancer prevention interventions, including education, screening, and treatment

Rapid translocation of nanoparticles from the lung airspaces to the body

Nano-size particles show promise for pulmonary drug delivery, yet their behavior after deposition in the lung remains poorly understood. In this study, a series of near-infrared (NIR) fluorescent nanoparticles were systematically varied in chemical composition, shape, size and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that nanoparticles with hydrodynamic diameter (HD) less than ≈34 nm and a noncationic surface charge translocate rapidly from the lung to mediastinal lymph nodes. Nanoparticles of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings for drug delivery, air pollution and carcinogenesis

Hematogenous Metastasis of Ovarian Cancer: Rethinking Mode of Spread

SummaryOvarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis

YM155 Induces EGFR Suppression in Pancreatic Cancer Cells

YM155, which inhibits the anti-apoptotic protein survivin, is known to exert anti-tumor effects in various cancers, including prostate and lung cancer. However, there are few reports describing the inhibitory effect of YM155 on human pancreatic cancers that highly express survivin. Here, we tested the effects of YM155 on a variety of cancer cell lines, including pancreatic cancer cells. We found that YM155 exerts an anti-proliferative effect in pancreatic cancer cells, inducing cell death through suppression of XIAP (X-linked inhibitor of apoptosis) as well as survivin without affecting the anti-apoptotic proteins Bcl-xL or Mcl-1. YM155 also inhibited tumor growth in vivo, reducing the size of pancreatic cancer cell line MIAPaCa-2 xenografts by 77.1% on day 31. Western blot analyses further showed that YM155 downregulated phosphoinoside 3-kinase (PI3K) expression and reduced the levels of phosphorylated (activated) extracellular signal-regulated kinase (ERK) and STAT3 (signal transducer and activator of transcription 3) in PANC-1 cells. Interestingly, we also found that YM155 downregulated the epidermal growth factor receptor (EGFR) in various cancer cell lines and induced the EGFR phosphorylation and ubiquitination of EGFR in PANC-1 cells. YM155 also modestly promoted the ubiquitination of survivin and XIAP. Therefore, YM155 acts through modulation of EGFR and survivin expression to subsequently reduce survival. We suggest that YM155 has potential as a therapeutic agent in the treatment of pancreatic cancer

High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

<p>Abstract</p> <p>Background</p> <p>Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal β-cell line, INS-1E.</p> <p>Methods</p> <p>The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed.</p> <p>Results</p> <p>Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 μM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction.</p> <p>Conclusions</p> <p>Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.</p